American Journal of Obstetrics & Gynecology
Volume 198, Issue 3 , Pages 281.e1-281.e5, March 2008

Maternal C-reactive protein and developmental programming of atherosclerosis

  • Antonio Liguori, MD

      Affiliations

    • Regional Hospital of Pellegrini and Loreto Crispi Hospital, 2nd School of Medicine, Federico II University, Naples, Italy
    • ,
  • Francesco P. D’Armiento, MD

      Affiliations

    • Division of Human Pathology, 2nd School of Medicine, Federico II University, Naples, Italy
    • ,
  • Antonio Palagiano, MD

      Affiliations

    • Division of Obstetrics and Gynecology, Department of General Pathology and Excellence Research Center on Cardiovascular Diseases, 1st School of Medicine, II University of Naples, Naples, Italy
    • ,
  • Wulf Palinski, MD

      Affiliations

    • Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA.
    • ,
  • Claudio Napoli, MD, PhD

      Affiliations

    • Division of Clinical Pathology, Department of General Pathology and Excellence Research Center on Cardiovascular Diseases, 1st School of Medicine, II University of Naples, Naples, Italy
    • Corresponding Author InformationReprints: Prof Claudio Napoli, Department of General Pathology, Division of Clinical Pathology and Excellence Research Center on Cardiovascular Diseases, 1st School of Medicine, II University of Naples, Complesso S. Andrea delle Dame 80138 Naples, Italy.

Received 26 April 2007; accepted 14 November 2007.

Article Outline

Objective

Maternal hypercholesterolemia during pregnancy enhances the susceptibility to atherosclerosis in their offspring by oxidation-dependent mechanisms. The present study investigated whether maternal C-reactive protein (CRP) level, which is an indicator of inflammation and cardiovascular risk, or smoking, which enhances oxidative stress, predict the in utero programming of atherosclerosis.

Study Design

Subsets of patients from the Fate of Early Lesions in Childhood study (156 normocholesterolemic children) were examined at autopsy, classified by maternal cholesterol levels during pregnancy. Maternal CRP level was correlated with maternal cholesterol and aortic atherosclerosis of children.

Results

CRP level was elevated in hypercholesterolemic mothers and showed significant correlation with atherogenesis in children in univariate and multivariate analysis. However, many hypercholesterolemic mothers did not have elevated CRP levels. Smoking only correlated in univariate analysis.

Conclusion

CRP level during pregnancy is a predictor of increased atherogenesis in children of hypercholesterolemic mothers, albeit a weaker one than maternal cholesterol. In the presence of hypercholesterolemia, maternal smoking does not further enhance atherogenic programming.

Key words: atherosclerosis, CRP, developmental programming, inflammation, maternal hypercholesterolemia, oxidative stress

 

Extensive epidemiologic evidence suggests that in utero conditions influence the susceptibility to hypertension, diabetes mellitus, and cardiovascular disease later in life.1, 2 Although most epidemiologic studies have focused on outcome parameters of impaired intrauterine growth (such as small birthweight, which may result from a range of pathogenetically distinct causes), specific maternal conditions have been identified that program increased susceptibility to atherosclerosis in adult offspring. One such condition is maternal hypercholesterolemia.3, 4 Both temporary hypercholesterolemia during pregnancy and chronic maternal hypercholesterolemia enhance the formation of early atherosclerotic lesions (fatty streaks) in human fetal aortas,5 and studies in experimental models with diet-induced hypercholesterolemia showed that the size of these lesions at birth is proportional to the maternal cholesterol level.6, 7 The first indication that maternal hypercholesterolemia also influences the postnatal susceptibility to atherosclerosis was provided by the Fate of Early Lesions in Childhood (FELIC) study, which was an autopsy study in normocholesterolemic children.8 Although fetal fatty streaks may regress partially in the perinatal period, when cholesterol levels are very low, children of hypercholesterolemic mothers showed accelerated progression of atherosclerosis in the aortic arch and abdominal aorta that could not be explained by conventional risk factors. Although the mechanisms of in utero programming remain largely unknown, there is a strong rationale to suspect the involvement of inflammatory processes that are analogous to those promoting atherosclerosis in adults.9 Indeed, plasma and arteries of human and animal offspring of hypercholesterolemic mothers contain high levels of proinflammatory lipid peroxidation products.5, 6, 7, 8 Conversely, maternal treatment with an antioxidant, vitamin E, prevents atherogenic in utero programming.7, 10

For Editors’ Commentary, see Table of Contents

C-reactive protein (CRP), a nonspecific acute-phase reactant and downstream biomarker of proinflammatory cytokines, has gained much attention as a surrogate measure of the inflammation and shows greater predictive power for cardiovascular disease than conventional lipid parameters, such as total and low-density lipoprotein cholesterol or the low-density lipoprotein/high-density lipoprotein ratio.11, 12, 13, 14, 15 CRP level also reflects the rapid changes in plasma cholesterol that are achieved by statin treatment16, 17 and thus presumably the reduced pathogenic effects of hypercholesterolemia and ensuing oxidative stress. Direct pathogenic effects of CRP on proatherogenic mechanisms have also been reported, but their influence in humans has not been established. For example, CRP modulates complement activation,18, 19, 20 enhances endothelial inflammation and expression of angiotensin 1 receptors,21, 22 and promotes apoptosis of vascular smooth muscle cells.23 We therefore used specimen and data from the FELIC study to investigate whether maternal CRP level also predicts developmental programming of atherosclerosis in the children. The aim of this study was to determine whether maternal CRP level or smoking were associated with atherosclerosis in the infant.

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Materials and Methods 

Subjects and study design 

A detailed description of the design of the FELIC study, patient population, and methods that were used to determine lipid parameters and atherosclerosis in children has been published.8 In brief, 156 normocholesterolemic children, ages 1-14 years, who died of acute, mostly traumatic, causes and underwent medicolegal autopsy were classified into 2 groups, depending exclusively on their mothers’ cholesterol levels during pregnancy. The latter were the mean of 3-4 prenatal examinations that were obtained from the medical records. Total cholesterol had been determined routinely in all maternal subjects but not at identical time points and not by the same laboratory. Given that the use of mean cholesterol values compensates for some of this temporal variability and that they were also used in the FELIC study, we used them for all present statistical analysis, except for the assessment of the correlation between CRP and cholesterol levels, for which cholesterol data from the same time point as CRP were used. Exclusion criteria were preeclampsia, acute infections, or intrauterine infections during pregnancy, as far as noted in medical records. In the FELIC study, maternal records that contain reliable cholesterol data could be obtained from 97 hypercholesterolemic and 59 age-matched normocholesterolemic mothers. The extent of atherosclerosis in all 156 children was determined by computer-assisted morphometry in 30 cross-sections each through the aortic arch and abdominal aorta. Maternal CRP level and smoking during pregnancy (yes/no) were obtained newly from medical records. However, CRP data were far less complete than cholesterol data. We therefore chose a single time point at which CRP data were available for the greatest number of subjects and used this for all analyses. Concentrations of CRP in plasma samples were obtained with a validated high-sensitivity immunoturbidimetric assay on the Hitachi 911 analyzer (Roche Diagnostics GMBH; Penzburg, Germany) with the use of reagents and calibrators from Denka Seiken (Niigata, Japan). Overall, the interassay coefficients of variability at concentrations of 0.90, 3.05, and 13.45 mg/L were 2.78%, 1.56%, and 1.05%, respectively. This assay had a sensitivity of 0.025 mg/L.

We initially compared CRP levels between the 2 maternal groups defined in the Lancet study. For further analyses (in particular, multiple regression analysis of the correlation between maternal CRP level, smoking, and total cholesterol with offspring atherosclerosis), data from both groups were combined and analyzed together, and actual maternal cholesterol levels were used. Case numbers for each analysis vary, because not all maternal records contained all of the parameters that were assessed.

Statistical analysis 

Maternal total cholesterol and CRP levels were compared by unpaired t test and linear correlation. The cumulative lesion areas in the aortic arch and abdominal aorta are correlated highly and were condensed into a single parameter, with the use of principal-components analysis of log-transformed lesion sizes. The first principal component accounted for more than 98.5% of the variation of the data (Eigen value, 1.97). We then performed multiple stepwise linear regression analysis with maternal risk factors, using pooled data from children of both normocholesterolemic and hypercholesterolemic mothers. The criteria to be entered into the stepwise model were an enter value of 0.05 and an elimination value of 0.10. From the resultant model, we tested individual covariates with Bonferroni-adjusted criteria for significance. P < .05 was considered significant. All statistical evaluations were performed with SPSS statistical software (v 13; SPSS Inc, Chicago, IL). Data are reported as means ± SEM.

The FELIC study and its present extension were approved by the human ethics committee of the University of Naples and the University of California, San Diego. Informed consent was obtained from all participating mothers.

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Results 

By definition, maternal cholesterol levels in the second to third trimester of pregnancy were significantly greater in the hypercholesterolemic than the normocholesterolemic maternal group (194.9 ± 2.9 mg/dL vs 279.9 ± 3.4 mg/dL; P < .000001). Maternal CRP levels were also much greater in hypercholesterolemic mothers (6.93 ± 0.36 mg/dL vs 4.68 ± 0.14 mg/dL; P < .000001; Figure 1). Interestingly, less than one-half of the hypercholesterolemic mothers had substantially elevated CRP levels (> 8 mg/dL).

  • View full-size image.
  • FIGURE 1. 

    CRP levels are significantly greater in the hypercholesterolemic than in the normocholesterolemic, group of mothers

  • Note that the maternal classification in the FELIC study was based on the average of 3-4 cholesterol determinations throughout pregnancy, whereas the total cholesterol data shown here represent corresponding measurements that were obtained during a single prenatal examination. Data represent all normo- and hypercholesterolemic mothers (n = 51 and 87, respectively) for whom both CRP and cholesterol data were available.

  • Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

The correlation between maternal CRP and plasma cholesterol levels in a subset of mothers (n = 89) for which both values could be obtained from medical records of the same prenatal examination is shown in Figure 2. The percentage of mothers who smoked during pregnancy was much greater in the hypercholesterolemic group than in the normocholesterolemic group (58.6% vs 38.5%), whereas the average number of cigarettes per day per smoker was similar. CRP also correlated significantly with maternal smoking in univariate analysis (R2 = 0.223; P < .0005). When CRP level was used as a dependable parameter in multivariate analysis, both maternal plasma cholesterol level and smoking remained significant (R2 = 0.408; P < .0005; standardized beta values 0.468 and 0.370, respectively).

  • View full-size image.
  • FIGURE 2. 

    Maternal plasma cholesterol level correlates with maternal CRP level during pregnancy

  • Data represent all mothers for whom both data were available at the same time point (n = 89). In contrast to all other analyses, cholesterol levels that were obtained at the same time point as CRP level were used instead of mean cholesterol levels.

  • Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

The FELIC study had indicated a strong correlation of atherosclerosis with age (Figure 3), which must be kept in mind when assessing correlations of maternal factors with non–age-corrected atherosclerosis data, such as the composite measure of atherosclerosis in the arch and abdominal aorta of children. Nevertheless, in addition to factors previously established as significant (ie, the age of the child [R2 = 0.536; P < .0005], the maternal group [R2 = 0.368; P < .0005], and maternal cholesterol level [R2 = 0.343; P < .0005]), maternal CRP level (R2 = 0.173; P < .0005; Figure 4) and maternal smoking (R2 = 0.084; P < .001) showed significant correlation with offspring atherosclerosis in univariate analysis.

  • View full-size image.
  • FIGURE 3. 

    Atherosclerosis progresses much faster in children of mothers who were hypercholesterolemic during pregnancy

  • Examples shown are the cumulative areas of atherosclerotic lesions in 30 cross-sections through the aortic arch (n = 97 and 59 for children of hyper- and normocholesterolemic mothers, respectively).8

  • Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

  • View full-size image.
  • FIGURE 4. 

    Maternal CRP level correlates with atherosclerosis in the child

  • Atherosclerosis that is indicated as the log-transformed first component was determined from mean cross-sectional lesion areas that were measured in the aortic arch and abdominal aorta. Note that atherosclerosis was not corrected for the age of the children and therefore shows considerable variability. Data reflect all mother/child pairs for whom maternal CRP level was known (n = 136).

  • Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

Significant parameters (child age, maternal total cholesterol, CRP, and smoking) were then included in a stepwise multiple regression analysis. Note that, in contrast to the FELIC study, we used the single maternal cholesterol value that was measured at the same time as CRP level, instead of the (highly correlated) maternal group, which was defined by the average maternal cholesterol level during multiple prenatal examinations. As shown in the Table, CRP level remained significant in the multiple regression analysis but showed a low beta factor. Smoking was not significant. Although maternal cholesterol level had a higher correlation than CRP level for childhood atherosclerosis, when cholesterol was removed from the multiple regression analysis, the age of the child and maternal CRP level together still predicted 68% of the atherosclerosis (P < .0005).

TABLE. Stepwise linear regression analysis with the use of a composite measure of atherosclerosis in the aortic arch and abdominal aorta as outcome parameter and factors that were correlated significantly with it in univariate analysis as predictors
ModelR2Standard error of the estimateSignificance of modelaStandardized coefficient (beta)Significance of covariatea
1. Age of child0.4890.688.00050.699.0005
2. Age of child0.8720.343.00050.732.0005
Maternal cholesterol 0.622.0005
3. Age of child0.8840.331.00050.740.0005
Maternal cholesterol 0.562.0005
Maternal CRP 0.116.009

Maternal cholesterol level, age of child, and atherosclerosis, 156 patients; maternal smoking, 154 patients; maternal CRP level, 136 patients.

Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

aProbability value.

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Comment 

Evidence from both human studies and experimental models indicates that maternal hypercholesterolemia programs increased susceptibility to atherosclerosis later in life.5, 7, 8, 24, 25, 26, 27 Unfortunately, maternal hypercholesterolemia is not determined routinely during pregnancy in most Western countries, with the notable exception of Italy, where it is part of the standard clinical laboratory tests that are performed during prenatal examinations.28 Although the mechanisms of developmental programming remain largely unknown, they are clearly dependent on oxidative stress, which is raised both by maternal hypercholesterolemia and smoking.3, 5, 6, 7, 10, 29, 30, 31, 32, 33 Oxidative stress affects the expression of many genes that influence recruitment, differentiation, and secretory activity of macrophages and T cells; conversely, increased inflammation promotes oxidative stress. It was tempting therefore to assume that, in the absence of cholesterol data, elevated maternal levels of CRP, which is a marker of inflammation, might be a surrogate indicator of the atherosclerosis risk of children. The present results indeed establish that maternal CRP level that is measured during the late second/early third trimester is elevated in hypercholesterolemic mothers and that it correlates with the extent of atherogenesis in children, both in univariate and multiple regression analysis. However, CRP level was a lesser indicator of atherogenic programming than maternal cholesterol level. A low beta factor of maternal CRP also makes it unlikely that the postulated atherogenic effects of CRP contribute substantially to in utero programming. It is tempting to conclude that CRP level merely reflects the inflammation that is concomitant with hypercholesterolemia. On the other hand, elevated CRP level is not specific for atherosclerosis, and CRP levels may be confounded by a number of unrelated conditions, such as maternal infections, that may not affect in utero programming. Elevated CRP levels may be a retrospective indicator of postnatal atherogenic risk, where cholesterol levels were not determined, and may prompt cholesterol determination, if detected before or during pregnancy.

Maternal smoking, which may induce atherogenic programming in normocholesterolemic animals,30 also correlated with atherosclerosis in children but lost significance when assessed together with maternal hypercholesterolemia. This suggests that oxidative stress–ensuing hypercholesterolemia by itself is more than enough to trigger atherogenic programming in the fetus and that smoking does not further enhance it sufficiently to become an independent predictor.

Limitations include the retrospective nature of the FELIC study and the ensuing need to rely on medical records for maternal data during pregnancy. The fact that these data were generated by a number of different clinical laboratories over a 14-year period may have increased variability. The retrospective nature of the study also made it impossible to supplement maternal data during pregnancy by measurements of other lipoproteins, in particular high-density lipoprotein, parameters of oxidative stress (to validate smoking history), and other parameters of inflammation, such as isoprostanes or antibody titers to oxidation-specific epitopes. In particular, uterine infections or general infections and other conditions that raise CRP level may not have been documented in maternal medical records, and their confounding effect may have been underestimated. Furthermore, not all parameters were available in all of the 156 mothers and their children, which reduced the power of the analysis. Finally, the incidence of other maternal conditions that potentially affect oxidative stress, such as maternal diabetes mellitus, was too low to yield reliable data for CRP. Ideally, the association of maternal risk factors with atherogenic programming and coronary heart disease should be assessed in prospective studies, but such studies would have to be very large and span at least 4 decades for cardiovascular outcomes (lesser periods, if surrogate measures of atherosclerosis are considered).

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 Cite this article as: Liguori A, D’Armiento FP, Palagiano A, Palinski W, Napoli C. Maternal C-reactive protein and developmental programming of atherosclerosis. Am J Obstet Gynecol 2008;198:281.e1-281.e5.

 This study was supported by grants from the Regione Campania and Ministery of University and Research P.R.I.N. 2006 (C. N.) and National Institutes of Health grants HL067792 and HL56989 (C. N. and W.P.).

PII: S0002-9378(07)02176-X

doi:10.1016/j.ajog.2007.11.027

American Journal of Obstetrics & Gynecology
Volume 198, Issue 3 , Pages 281.e1-281.e5, March 2008

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